New science uncovers how an unlikely culprit, Porphyromonas gingivalis (Pg) — the bacterium commonly associated with chronic gum disease — appears to drive Alzheimer's disease (AD) pathology. A paper published in Science Advances details how researchers identified Pg in the brains of patients with AD.
Infectious agents and development of Alzheimer's disease
According to Potempa, although infectious agents have been implicated in the development and progression of Alzheimer's disease, the evidence of causation hasn't been convincing. However, "we now have strong evidence connecting P. gingivalisand Alzheimer's pathogenesis, but more research needs to be done before P. gingivalis is explicitly implicated in the causation or morbidity of AD.
"An even more notable aspect of this study is demonstration of the potential for a class of molecule therapies targeting major virulence factors to change the trajectory of AD, which seems to be epidemiologically and clinically associated with periodontitis," Potempa said.
In animal models, oral Pg infection led to brain colonization and increased production of amyloid beta (Aβ), a component of the amyloid plaques commonly associated with AD.The study team also found the organism's toxic enzymes, or gingipains, in the neurons of patients with AD. Gingipains are secreted and transported to outer bacterial membrane surfaces and have been shown to mediate the toxicity of Pg in a variety of cells.
Inhibiting COR388, reduced neuroinflammation
The team correlated the gingipain levels with pathology related to two markers: tau, a protein needed for normal neuronal function, and ubiquitin, a small protein tag that marks damaged proteins. In preclinical experiments, researchers demonstrated that by inhibiting the compound COR388, there was reduced bacterial load of an established Pgbrain infection, blocked Aβ42 production, reduced neuroinflammation and protected neurons in the hippocampus.
In October 2018, Cortexyme announced results from its Phase 1b clinical trial of COR388 at the 11th Clinical Trials in Alzheimer's Disease Conference. COR388 showed positive trends across several cognitive tests in patients suffering from AD, and Cortexyme plans to initiate a Phase 2 and 3 clinical trial of COR388 in mild to moderate AD in 2019.